Apoptotic and autophagic cell death induced by histone deacetylase inhibitors

Yufang Shao, Zhonghua Gao, Paul A. Marks, Xuejun Jiang

Research output: Contribution to journalArticle

465 Citations (Scopus)

Abstract

Histone deacetylase (HDAC) inhibitors can induce programmed cell death in cancer cells, although the underlying mechanism is obscure. In this study, we show that two distinct HDAC inhibitors, butyrate and suberoylanilide hydroxamic acid (SAHA), induced caspase-3 activation and cell death in multiple human cancer cell lines. The activation of caspase-3 was via the mitochondria/ cytochrome c-mediated apoptotic pathway because it was abrogated in mouse embryonic fibroblasts with knockout of Apaf-1, the essential mediator of the pathway. Overexpression of Bel-XL in HeLa cells also blocked caspase activation by the HDAC inhibitors. Nevertheless, Apaf-1 knockout, overexpression of Bel-XL, and pharmacological inhibition of caspase activity did not prevent SAHA and butyrate-induced cell death. The cells undergoing such caspase-independent death had unambiguous morphological features of autophagic cell death. Therefore, HDAC inhibitors can induce both mitochondria-mediated apoptosis and caspase-independent autophagic cell death. Induction of autophagic cell death by HDAC inhibitors has clear clinical implications in treating cancers with apoptotic defects.

Original languageEnglish (US)
Pages (from-to)18030-18035
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number52
DOIs
StatePublished - Dec 28 2004

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Histone Deacetylase Inhibitors
Autophagy
Caspases
Cell Death
Butyrates
Caspase 3
Mitochondria
Neoplasms
Cytochromes c
HeLa Cells
Fibroblasts
Pharmacology
Apoptosis
Cell Line

All Science Journal Classification (ASJC) codes

  • General

Cite this

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abstract = "Histone deacetylase (HDAC) inhibitors can induce programmed cell death in cancer cells, although the underlying mechanism is obscure. In this study, we show that two distinct HDAC inhibitors, butyrate and suberoylanilide hydroxamic acid (SAHA), induced caspase-3 activation and cell death in multiple human cancer cell lines. The activation of caspase-3 was via the mitochondria/ cytochrome c-mediated apoptotic pathway because it was abrogated in mouse embryonic fibroblasts with knockout of Apaf-1, the essential mediator of the pathway. Overexpression of Bel-XL in HeLa cells also blocked caspase activation by the HDAC inhibitors. Nevertheless, Apaf-1 knockout, overexpression of Bel-XL, and pharmacological inhibition of caspase activity did not prevent SAHA and butyrate-induced cell death. The cells undergoing such caspase-independent death had unambiguous morphological features of autophagic cell death. Therefore, HDAC inhibitors can induce both mitochondria-mediated apoptosis and caspase-independent autophagic cell death. Induction of autophagic cell death by HDAC inhibitors has clear clinical implications in treating cancers with apoptotic defects.",
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Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. / Shao, Yufang; Gao, Zhonghua; Marks, Paul A.; Jiang, Xuejun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 52, 28.12.2004, p. 18030-18035.

Research output: Contribution to journalArticle

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